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J Thome

Publications and source records attributed to J Thome.

At least 37 records · Page 2Linked to original sources
PubMed2000

Promoter polymorphism of the 5-HT transporter and Alzheimer's disease.

The role of the deletion/insertion polymorphism within the promoter region of the serotonin transporter gene (5-HTT) is under discussion as a potential genetic risk factor for Alzheimers's disease (AD). Here we report significant differences in the allelic distribution of this polymorphism with a higher frequency of the short variant allele in AD patients when compared to controls. This difference was independent of the apolipoproteinE genotype. Thus, our study supports the notion that genetic alterations in the serontonergic neurotransmitter system may be involved in the etiopathogenesis of AD. However, given the reported negative findings, we are presently trying to identify diagnostic subgroups for which the 5-HTT promoter polymorphism represents a susceptibility locus.

Alleles↗
PubMed2000

cAMP response element-mediated gene transcription is upregulated by chronic antidepressant treatment.

Regulation of gene transcription via the cAMP-mediated second messenger pathway has been implicated in the actions of antidepressant drugs, but studies to date have not demonstrated such an effect in vivo. To directly study the regulation of cAMP response element (CRE)-mediated gene transcription by antidepressants, transgenic mice with a CRE-LacZ reporter gene construct were administered one of three different classes of antidepressants: a norepinephrine selective reuptake inhibitor (desipramine), a serotonin selective reuptake inhibitor (fluoxetine), or a monoamine oxidase inhibitor (tranylcypromine). Chronic, but not acute, administration of these antidepressants significantly increased CRE-mediated gene transcription, as well as the phosphorylation of CRE binding protein (CREB), in several limbic brain regions thought to mediate the action of antidepressants, including the cerebral cortex, hippocampus, amygdala, and hypothalamus. These results demonstrate that chronic antidepressant treatment induces CRE-mediated gene expression in a neuroanatomically differentiated pattern and further elucidate the molecular mechanisms underlying the actions of these widely used therapeutic agents.

Animals↗
PubMed2000

Upregulation of galanin binding sites and GalR1 mRNA levels in the mouse locus coeruleus following chronic morphine treatments and precipitated morphine withdrawal.

The neuropeptide galanin and its receptors are expressed in the locus coeruleus (LC), a brain area associated with drug dependence and withdrawal. Although galanin peptide mRNA levels do not change during withdrawal, it is not known whether galanin receptor levels are regulated following opiate withdrawal. This study demonstrates that galanin binding in the LC is upregulated by chronic-intermittent morphine administration or by precipitated withdrawal, but not by acute morphine treatment, suggesting that increased activity in the LC may be able to regulate galanin binding sites. Moreover, the increase in galanin binding sites seems to be caused by increased transcription or stabilization of the galanin receptor 1 (GalR1) gene, because there is a dramatic increase in mRNA levels following withdrawal in the LC. It is, therefore, possible that the increase in GalR1 could be an adaptive mechanism that leads to regulation of cAMP levels and possibly firing rate of LC neurons.

Animals↗
PubMed2000

Genome polymorphism and alcoholism.

Different gene variants have been identified as risk or protective factors in alcoholism. The genes coding for dopamine receptors, serotonin transporters, and dehydrogenases represent susceptibility loci for addictive behaviour. However, alcoholism represents a complex psychiatric symptomatology which is caused by multiple factors, both genetic and environmental. Furthermore, there are probably different subtypes of alcoholism each with a distinct pathophysiology, and thus a different genetic background. Genetic research can help to identify such subtypes, which may require different therapeutic approaches. However, gene polymorphisms are not only responsible for a predisposition to alcoholism, but also for personality traits which influence the likelihood of developing addictive behaviour. Moreover, genetic polymorphisms are probably involved in the way an individual responds to treatment. Also, the severity of secondary diseases resulting from chronic alcohol uptake may depend on the genetic makeup of an individual. New treatment strategies focusing on genes contributing towards drug and alcohol dependence (such as gene therapy) are already under examination in animal models. However, further research is required before these developments will considerably change today's clinical handling of alcoholism.

Alcoholism↗
PubMed2000

Correlation between Apolipoprotein-E polymorphism and Alzheimer's disease pathology.

Alzheimer's disease (AD) and small vessel disease dementia (SVDD) are common causes of dementia. The ApoE genotype has been proposed as a risk factor for AD. The frequency of the three ApoE alleles was correlated with the neuropathological changes of AD (senile plaques, neurofibrillary tangles and amyloid angiopathy) and SVDD (status lacunaris, status cribosus, leucoencephalopathy, micronecrosis and vascular fibrohyalinosis) in order to validate previous ApoE genotyping results in AD and to identify pre-clinical AD. Representative cerebral regions (cortex, gyrus cinguli, putamen, hippocampus, white matter) from 28 AD cases, 7 SVDD and 38 non-neurological controls were studied using classical histological techniques and immunohistochemistry for tau protein and amyloid-beta. The frequency of the ApoE allele 4 was significantly increased not only in AD patients but also in aged controls. However, following a detailed histopathological examination was found 62% of this group to exhibit histological changes associated with AD in limited brain areas (entorhinal region, hippocampus and adjacent temporal cortex or entorhinal region and hippocampus, or only in the entorhinal region), but 87% of these cases were found to be ApoE4 positive. The significant differences found in the distribution of ApoE allele frequencies were more marked when these cases were excluded from the control group and included as AD cases. In contrast, the frequency of the ApoE allele 2 is significantly increased in SVDD patients. Using histological techniques we confirmed the clinical diagnoses of all cases and classified the AD patients according to the severity of cortical pathology related to AD, while re-grouping from the control group those cases which had no clinical history of the disease but exhibited typical AD and SVDD histological lessions which could be considered as "pre-clinical" forms of these diseases.

Journal Article↗
PubMed1999

Neural plasticity to stress and antidepressant treatment.

Adaptations at the cellular and molecular levels in response to stress and antidepressant treatment could represent a form of neural plasticity that contributes to the pathophysiology and treatment of depression. At the cellular level, atrophy and death of stress-vulnerable neurons in the hippocampus, as well as decreased neurogenesis of hippocampal neurons, has been reported in preclinical studies. Clinical studies also provide evidence for atrophy and cell death in the hippocampus, as well as the prefrontal cortex. It is possible that antidepressant treatment could oppose these adverse cellular effects, which may be regarded as a loss of neural plasticity, by blocking or reversing the atrophy of hippocampal neurons and by increasing cell survival and function. The molecular mechanisms underlying these effects are discussed, including the role of the cAMP signal transduction cascade and neurotrophic factors.

Antidepressive Agents↗
PubMed1999

Polymorphisms of the human apolipoprotein E promoter and bleomycin hydrolase gene: risk factors for Alzheimer's dementia?

In addition to the apolipoprotein E (ApoE) tri-allele polymorphism, genetic variants of the apolipoprotein E promoter (-491A/T) and the bleomycin hydrolase (BH-PEN) gene have also been proposed as genetic risk factors for Alzheimer's dementia (AD). Since reports about the relevance of these polymorphisms for the pathogenesis of AD have been contradictory, we performed an association study with some modifications. First, the control group in this study was made up of non-demented psychiatric inpatients, rather than healthy subjects. This procedure allows the specificity of the relationship between a given genotype and AD (as opposed to other psychiatric disorders) to be determined. Second, as an alternative to preexisting relatively time consuming techniques, BH-PEN polymorphism was determined using a simplified method based on PCR genotyping. We found a significant linkage disequilibrium between the -491A/T and ApoE polymorphisms. However, no direct association was observed between the -491A/T or BH-PEN polymorphism and AD.

Alleles↗
PubMed1999

Dopamine D3 receptor gene polymorphism and alcohol dependence: relation to personality rating.

Hereditary dopaminergic mechanisms have been implicated in the aetiology of alcoholism. For this study, the distribution of a dopamine D3 receptor gene polymorphism (Ball) has been investigated in patients suffering from alcohol dependence, and compared with non-dependent controls. The allele A1 occurred significantly more frequently among patients compared to controls. Patients with the genotype A1/A2 showed significantly higher novelty seeking (NS) scores in the tridimensional personality questionnaire (TPQ) than patients with the genotype A1/A1. The distribution of patients with high and low NS scores in heterozygotes (A1/A2) did not follow a random distribution. There were significantly more individuals with higher NS scores, and fewer individuals with lower NS scores than expected. The results of this study support the hypothesis of a genetically determined involvement of the dopaminergic system in alcohol dependence. This is probably related to the modulation of personality traits. The observed effects are relatively small, but statistically significant. Thus, the genetics of the dopaminergic neurotransmitter system alone cannot explain the aetiopathogenesis of alcoholism.

Adult↗
PubMed1998

Regulation of cocaine reward by CREB.

Cocaine regulates the transcription factor CREB (adenosine 3', 5'-monophosphate response element binding protein) in rat nucleus accumbens, a brain region that is important for addiction. Overexpression of CREB in this region decreases the rewarding effects of cocaine and makes low doses of the drug aversive. Conversely, overexpression of a dominant-negative mutant CREB increases the rewarding effects of cocaine. Altered transcription of dynorphin likely contributes to these effects: Its expression is increased by overexpression of CREB and decreased by overexpression of mutant CREB. Moreover, blockade of kappa opioid receptors (on which dynorphin acts) antagonizes the negative effect of CREB on cocaine reward. These results identify an intracellular cascade-culminating in gene expression-through which exposure to cocaine modifies subsequent responsiveness to the drug.

Animals↗
PubMed1998

Growth hormone response to placebo, apomorphine and growth hormone releasing hormone in abstinent alcoholics and control subjects.

Abstinent alcoholics and control subjects were challenged with placebo (saline), growth hormone releasing hormone (GHRH) and apomorphine (APO). While both groups did not differ in their growth hormone response (HGH) to placebo and GHRH, the alcoholics revealed a significant lower HGH response to dopamine receptor stimulation with APO. These findings provide no evidence that in abstinent alcoholics HGH blunting after dopamine receptor stimulation could be related to an alteration at the pituitary level but they give neuroendocrinological support to the hypothesis of a lower dopamine receptor sensitivity in abstinent alcoholics.

Adult↗
PubMed1998

Free radicals in Alzheimer's dementia: currently available therapeutic strategies.

Substantial evidence now exists that oxidative stress may play an important role in the etiopathogenesis of DAT. The different sources of oxidative stress in DAT are suggesting several pharmacological opportunities for influencing the disease. It is possible to distinguish 2 major types of possible therapeutic agents according to their pharmacological point of attack. 1. Radical scavengers, agents directly interacting with free radicals. Candidates of this type are gingko biloba, vitamins A, C, E and estrogen. 2. Antioxidants, which are able to prevent or decrease the production of free radicals by use of specific neuropharmacological properties. Candidates are selegiline, a MAO-B inhibitor well established in the therapy of Parkinson's disease, and tenilsetam, which is believed to be an AGE-inhibitor. Recent in vitro studies have demonstrated the efficacy of both types of therapeutic agents by preventing or delaying oxidative neural damage. Some clinical data exist regarding the antidementive properties particularly in terms of gingko biloba, selegiline and vitamin E. The efficacy studies about these compounds seem to indicate a promising future strategy in the therapy of DAT. But it is too early to draw definite conclusions since it is well known that all of our candidate substances do not act specifically as radical scavengers or antioxidants.

Alzheimer Disease↗
PubMed1998

Neurotrophic factors and the maldevelopmental hypothesis of schizophrenic psychoses. Review article.

The maldevelopmental model of schizophrenia postulates pathological alterations in embryonal neurogenesis as the etiopathogenetic basis of schizophrenic psychosis; the neurotrophic factor hypothesis explains these changes as the result of disturbances of processes involving the trophic factors. Neurotransmitter deficits are thereby interpreted as epiphenomena of underlying neurotrophic factor deficacy. The functional systems of the various neurotrophic factors are characterized by complex interaction mechanisms. Both primary genetic alterations, and secondary impairments, induced by exogene noxae, of the receptors and signal transducers associated with neurotrophic factors, as well as of the neurotrophic factors themselves are possible. Preliminary clinical studies indicate that schizophrenic psychoses may be associated with changes in the genetic code of certain neurotrophic factors. Various phenomena typical of the schizophrenic psychoses can be interpreted according to the neurotrophic factor hypothesis.

Animals↗
PubMed1997

Variants in neurotrophic factor genes and schizophrenic psychoses: no associations in a Spanish population.

Possible associations between schizophrenic psychoses, a ciliary neurotrophic factor (CNTF) null mutation and a neurotrophin in 3 (NT3) bi-allele polymorphism were investigated in a Spanish population. The sample consisted of 107 patients suffering from schizophrenic psychoses and 100 healthy volunteers. There was no statistical difference in the frequencies of the mutant CNTF allele in the index and control groups (0.125 vs. 0.121). The frequency of the rare NT3 allele (Glu) was very low and similar in both groups (0.005). Previous findings supporting the involvement of these genetic markers in the pathogenesis of schizophrenic psychoses were thus not confirmed. In light of neurodevelopmental hypotheses of schizophrenia, however, genes coding for neurotrophic factors remain interesting susceptibility loci in schizophrenia research. Subsequent studies should not focus exclusively on genetic alterations but also take into account secondary changes of the neurotrophic factor system at the mRNA and protein levels. Further, the current unsatisfying operationalized classification of the heterogeneous syndrome 'schizophrenia' remains a crucial problem that could be partially resolved by introducing more differentiated diagnoses defined on the basis of neurobiological criteria.

Ciliary Neurotrophic Factor↗
PubMed1997

Time course of manganese superoxide dismutase concentrations in serum of alcohol-dependent patients during abstinence.

Mean manganese superoxide dismutase (Mn-SOD) concentrations in the serum of patients suffering from alcohol dependence is almost twice as high as in serum of non-dependent controls. In order to investigate the time course of this parameter during abstinence, we determined it at different time points. Patients had mean Mn-SOD serum concentrations (+/-S.D.) of 150.4 +/- 76.3, 121.1 +/- 40.7, 94.6 +/- 37.8 micrograms/ml at 1, 10 and 40 days after abstinence compared to 76.3 +/- 16.9 micrograms/ml as mean Mn-SOD value in the control group. Although the Mn-SOD concentration tended to normalise during abstinence, the differences between index and control group remained significant up to the last measurement at day 40.

Adult↗
PubMed1997

A comparison of qEEG and HMPAO-SPECT in relation to the clinical severity of Alzheimer's disease.

Electroencephalographical studies have disclosed correlations between topographical features of Fast Fourier Transformation maps and the severity of Alzheimer's disease (DAT). The object of the present study was to explore the relations of HMPAO-SPECT and quantitative EEG (qEEG) with the severity of dementia. Twenty-three patients were included in the study. Spectral and topographical EEG parameters were compared with global and regional cerebral blood flow, and with psychometric measures of clinical severity. None of the regions of interest of the SPECT scans were significantly correlated with clinical severity. Low values in delta- and theta bands, however, were related to high scores on the Mini-Mental-State examination (P < 0.01), whereas the Syndrome-Kurz test correlated inversely with the power values in the alpha and beta band. The global decrease in cerebral blood flow (CBF) was associated with a shift on the topographical alpha-centroids in the posterior direction (P < 0.01). In previous studies correlations between CBF and clinical severity were weak, indicating a high interindividual variance, or interactions with concomitant vascular lesions. Whereas SPECT is a well-established tool for the diagnosis of dementia, the present study indicates qEEG as a potential marker for the staging of the cognitive decline in DAT.

Aged↗
PubMed1997

Oxidative-stress associated parameters (lactoferrin, superoxide dismutases) in serum of patients with Alzheimer's disease.

In this case/control study, serum levels of oxidative stress related parameters such as Fe-binding lactoferrin (LTF), Mn- and Zn,Cu-superoxide dismutase (SOD) were determined by enzyme linked immunoassays in patients suffering from the Alzheimer's dementia as well as in non-demented controls. The Mn-SOD concentration was significantly (P<0.05, U-test) reduced in patients suffering from Alzheimer's disease if compared to non-demented controls. The other parameters investigated did not differ significantly between both groups. Our findings give evidence for the hypothesis of a disturbed free radical metabolism in Alzheimer's disease. The specificity of these results remains to be clarified. Further studies are needed to elucidate the relevance of oxidative stress in the etiopathogenesis of the Alzheimer's disease.

Aged↗
PubMed1997

Advanced glycation endproducts in ageing and Alzheimer's disease.

Accumulation of advanced glycation endproducts (AGE) in the brain is a feature of ageing and degeneration, especially in Alzheimer's disease (AD). Increased AGE levels explain many of the neuropathological and biochemical features of AD such as extensive protein crosslinking (beta-amyloid and MAP-tau), oxidative stress and neuronal cell death. Oxidative stress and AGEs initiate a positive feedback loop, where normal age-related changes develop into a pathophysiological cascade. Combined intervention using antioxidants, metal chelators, anti-inflammatory drugs and AGE-inhibitors may be a promising neuroprotective strategy.

Aging↗